Several publications are referenced in this application by numerals in parentheses in order to more fully describe the state of the art to which this invention pertains. Full citations for these references are found at the end of the specification. The disclosure of each of these publications is incorporated by reference herein.
Ischemic preconditioning functions as an endogenous protective mechanism which enhances the ability of myocardium to withstand injury from prologed ischemia. Transient ischemic events, which are sufficiently brief to avoid irreversibly damaging myocardium, initiate unidentified biochemical events which limit infarct size and the occurrence of reperfusion arrhythmias following prolonged myocardial ischemias (5).
A series of studies have shown that it is possible to induce ischemic preconditioning with a variety of pharmacological agents. Adenosine is released in large amounts during myocardial ischemia and mediates potentially important protective functions in the cardiovascular system (1,4,5,7,9,14,17,18,19,25). Adenosine can precondition the heart with reduction in the size of myocardial infarction (4,5,9,14,17,18). Intracoronary administration of adenosine during reperfusion following prolonged no-flow ischemia can also limit infarct size in the intact heart (1, 19).
Previous studies have shown that adenosine A.sub.1 and A.sub.3 receptor agonists can precondition the heart when administered before the onset of ischemia (4, 5, 9, 14, 17, 18). Other studies have shown that adenosine A.sub.2a receptor antagonists also enhance the cardioprotective effect of preconditioning (23). These agents effectively 1) reduce infarct size; and 2) improve left ventricular function when given during reperfusion (1, 19) or during both low-flow ischemia and reperfusion in isolated perfused heart (6, 21, 22).
Monophosphoryl lipid A (MLA), a relatively non-toxic derivative of endotoxin, has also been found to provide cardioprotection in a variety of animal models (43-45) when administered prior to an ischemic event. The mechanism of myocardial protection mediated by MLA has not yet been definitively elucidated. Other effective pharmacological preconditioning agents include K.sup.+ ATP channel openers and phorbol esters.
Intensive research efforts are currently focused on the development of agents and methods for treating and preventing cardiac diseases. The present invention is directed to such methods.